To explore a new concept of cancer chemotherapy utilizing diphtheria toxin as the chemotherapeutic agent in toxin immune individuals. This objective is based on our recent discovery that protein synthesis in some human and mouse tumor cells in vitro was much more sensitive to diphtheria toxin than cells from any of the normal human or mouse tissues tested (1). Furthermore the in vitro sensitivity to diphtheria toxin of Ehrlich-Lettre tumors correlated with the observation that Ehrlich-Lettre tumors regressed in mice with diphtheria toxin (1,2) but not diphtheria toxoid and that regression occurred even in the presence of antitoxin antibody (1). We wish to develop suitable animal models to evaluate the relative efficacy of diphtheria toxin therapy for tumors representative of different organ systems and cell types. We shall determine optimal conditions for toxin administration and antitoxin immunization. We intend to establish therapeutic parameters in experimental animals using tumors from animals and humans. As stated above some human tumor cells are more sensitive to inhibition of protein synthesis by diphtheria toxin than normal cells (1). Consequently the long-range objective of this proposal is, as we have discussed elsewhere (1), to apply the information gained from studies in animals to the use of diphtheria toxin as an anti-tumor agent in man. The immediate objectives of this study are but one aspect of the ultimate objective of our research program which is to apply toxin therapy to human neoplasms. Thus determining what types of human tumors are more sensitive to DT than normal tissues and the relationship of increased sensitivity to DT to other properties of transformed cells are outside the scope of this proposal but are being undertaken in our laboratories and will be correlated with the findings obtained in this study.